While hematopoietic stem cells have significant therapeutic potential, a limitation that has hindered their use in the clinic has been the development of graft-versus-host disease (GVHD) some days or weeks after the cell transplant. While significant advances have been made with regard to the treatment of GVHD following transplantation, there is still a need in the art for improved methods, particularly with respect to reducing mortality rates from GVHD. Conventional treatment of GVHD requires systemic immunosuppressive therapy with potent drugs such as corticosteroids and cyclosporine. Agents such as mycophenolate mofetil, rapamycin (sirolimus), imatinib, and rituximab are used in patients with steroid-refractory GVHD. However, these treatments have limited efficacy and often cause severe adverse effects. Only 50% of patients with GVHD are able to discontinue immunosuppressive treatment within 5 years after diagnosis, and 10% require continued treatment beyond 5 years. The remaining 40% die or develop recurrent malignancy before GVHD resolves. Five year survival rates of patients with high risk GVHD (platelet counts <100,000/microliter or progressive onset from GVHD) is only 40-50%. Thus, the development of innovative strategies to prevent and treat GVHD represents an important unmet clinical need.
Like, GVHD, autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, intestinal bowel disease, psoriasis, lupus, and Type 1 diabetes are characterized by an abnormal immune response directed against normal self tissues. Autoimmune diseases are characterized by production of autoreactive T cells and antibodies reactive with host tissues (autoantibodies). Traditional therapies for autoimmune disease include immunosuppressive agents that globally dampen immune responses. The benefits of such agents are often tempered by susceptibility to opportunistic infections, long-term risk of malignancy, toxicity and other unfavorable side effects. Thus, there is a need to develop a strategy to more specifically target the cellular mediators of both GVHD and autoimmune diseases.